Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC.

<div>Abstract<p>We explored the association between liver metastases, tumor CD8<sup>+</sup> T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non–small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) <i>P</i> ≤ 0.0001, and confirmed in the validation cohort (<i>P</i> = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; <i>P</i> < 0.0001). In a subset of biopsied patients (<i>n</i> = 62), liver metastasis was associated with reduced CD8<sup>+</sup> T-cell density at the invasive tumor margin (liver metastasis<sup>+</sup> group, <i>n</i> = 547 ± 164.8; liver metastasis<sup>−</sup> group, <i>n</i> = 1,441 ± 250.7; <i>P</i> < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4–2.0], compared with those without liver metastasis (<i>n</i> = 119, median PFS, 4.0 months; 95% CI, 2.1–5.1), <i>P</i> = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8<sup>+</sup> T-cell infiltration, providing a potential mechanism for this outcome. <i>Cancer Immunol Res; 5(5); 417–24. ©2017 AACR</i>.</p></div>

<div>Abstract<p>We explored the association between liver metastases, tumor CD8<sup>+</sup> T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non–small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) <i>P</i> ≤ 0.0001, and confirmed in the validation cohort (<i>P</i> = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; <i>P</i> < 0.0001). In a subset of biopsied patients (<i>n</i> = 62), liver metastasis was associated with reduced CD8<sup>+</sup> T-cell density at the invasive tumor margin (liver metastasis<sup>+</sup> group, <i>n</i> = 547 ± 164.8; liver metastasis<sup>−</sup> group, <i>n</i> = 1,441 ± 250.7; <i>P</i> < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4–2.0], compared with those without liver metastasis (<i>n</i> = 119, median PFS, 4.0 months; 95% CI, 2.1–5.1), <i>P</i> = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8<sup>+</sup> T-cell infiltration, providing a potential mechanism for this outcome. <i>Cancer Immunol Res; 5(5); 417–24. ©2017 AACR</i>.</p></div>

A recent study published in the New England Journal of Medicine by Pasi A. Jänne et al.1 presented the Phase II cohort results from a clinical trial (KRYSTAL-1, NCT03785249), which evaluated adagrasib (MRTX849, a KRASG12C inhibitor) in KRASG12C-mutated nonsmall-cell lung cancer (NSCLC) previously treated with chemotherapy and antiprogrammed death 1 (PD-1) or antiprogrammed death ligand 1 (PD-L1) therapy. Adagrasib showed encouraging efficacy and acceptable safety, offering novel therapeutic avenues for KRASG12C-mutated NSCLC (Figure 1A). This study enrolled 116 patients with histologically confirmed unresectable or metastatic NSCLC with KRASG12C mutation who had accepted treatment with at least one platinum-based chemotherapy regimen and immune checkpoint inhibitors (ICIs) therapy. 98.3% of the patients accepted both chemotherapy and immunotherapy previously. The patients received a 600-mg dose of adagrasib twice daily, with a fasted state. Among 112 patients with measurable disease at baseline, the confirmed objective response rate (ORR) was 42.9%. The median response duration of 48 patients with a response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival (PFS) among 112 evaluable patients was 6.5 months (95% CI, 4.7 to 8.4). The median overall survival (OS) was 12.6 months (95% CI, 9.2 to 19.2), with updated data on January 15, 2022. In 33 patients with radiographically evaluable CNS metastases, the intracranial confirmed ORR was 33.3% (95% CI, 18.0 to 51.8). 97.4% of the patients underwent treatment-related adverse events, the most common of which were diarrhea, nausea, vomiting, and fatigue, leading to a 6.9% drug discontinuation rate. The ORRs were similar across PD-L1 expression subgroups, indicating that the efficacy of adagrasib effectiveness was not affected by PD-L1 expression. The ORRs in patients with coalterations in STK11, KEAP1, TP53, and CDKN2A were satisfying (range 28.6%-58.3%). While the ORR in those who had STK11 wildtype with KEAP1 comutation was lower (14.3%). More evidence on this issue is warranted since precise stratification of KRAS-mutated NSCLC patients is necessary before clinical decisions. Adagrasib is a robust, orally available, small molecule covalent inhibitor binding to the KRASG12C cysteine 12 residue, locking the protein in its inactive GDP-bound conformation, thus blocking KRAS-dependent signaling and exerting antitumor efficacy in tumor models2 (Figure 1B). The registered interventional clinical trials of adagrasib in cancer were summarized (Figure 1C). As the first KRASG12C inhibitor approved by FDA (Food and Drug Administration), sotorasib yielded a durable clinical benefit in KRASG12C-mutated NSCLC (NCT03600883). In NSCLC, adagrasib was superior to sotorasib in ORR (sotorasib 37.1%, adagrasib 42.9%), and they were similar in median OS (sotorasib 12.5 months, adagrasib 12.6 months) and median PFS (sotorasib 6.8 months, adagrasib 6.5 months) (NCT03785249 and NCT03600883). In addition, pharmacologic differences between adagrasib and sotorasib are the drug half-life, dose-dependent extended exposure with adagrasib, and potential central nervous system (CNS) penetration of adagrasib. Approximately 27%-42% of KRASG12C-mutated NSCLC patients have CNS metastases at diagnosis and are of dismal prognosis. Under the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, Jänne et al.1 identified 42 patients with CNS metastases at baseline, the median intracranial PFS of whom was 5.4 months (95% CI, 3.3. to 11.6). A total of 33 patients of them could be evaluated radiographically, the intracranial confirmed ORR was 33.3% (95% CI, 18.0 to 51.8), and the median duration of intracranial response was 11.2 months (95% CI, 2.99 to not evaluable). In a previous report, sotorasib led to a 13% intracranial response rate in 16 KRASG12C-NSCLC patients with stable, treated CNS metastases (CodeBreaK 100, NCT03600883). However, the CNS penetration ability of adagrasib warrants further investigation since all patients with CNS metastases recruited were previously treated and neurologically stable, and the number of patients with CNS metastases was limited. The good news is that at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Mirati Therapeutics Inc announced the first clinical data demonstrating CNS-specific activity of KRASG12C inhibitor (adagrasib) in NSCLC patients with active and untreated CNS metastases (the Phase Ib cohort of NCT03785249): the intracranial ORR was approximately 32% under RANO-BM criteria and the intracranial disease control rate was about 84% (NCT03785249, Meeting Abstract | 2022 ASCO Annual Meeting II). The adoption of patients with active CNS disease in Jänne et al.'s study also received attention from Kotecha et.al, who gave their concerns and suggestions about this issue.3 We expect more evidence derived from large-scale cohorts. The efficacy comparisons we made between adagrasib and sotorasib were preliminary work based on the current data from different cohorts. More solid evidence about these comparisons should be referred to head-to-head RCTs (randomized control trials). In NSCLC, the KRASG12C mutation frequency is 14% in adenocarcinoma and 0.5%–4% in squamous carcinoma.1 Although most patients in the study of Jänne et al.1 were ECOG 1 and had previously received both chemotherapy and ICI therapy, the efficacy of adagrasib was better than traditional second-line chemotherapy. In NSCLC second-line docetaxel treatment, the ORR was 14%, the PFS was 3.0 months (IQR 1.4-6.9), and the median OS was 9.1 months (IQR 4.2-18.0) (NCT01168973). Therefore, adagrasib could bring hope to a substantial late-stage NSCLC patient irresponsive to traditional chemotherapy. We believe that the clinical outcome of adagrasib would be improved when applied at an earlier stage. The safety of adagrasib is acceptable. Although treatment-related adverse events were observed in 97.4% of the patients, the drug discontinuation rate was low (6.9%). The most common events were gastrointestinal-related events, similar to other KRASG12C inhibitors. We expect the ongoing evaluation of an additional dose level (400 mg orally twice daily)1 which might offer an opportunity to relieve the adverse events. Moreover, KRASG12C mutation occurs in 3%-4% of CRC (Colorectal Cancer). Durable blockade of KRASG12C might be of significance in CRC. In 2021, Weiss et al. reported that adagrasib demonstrated promising clinical efficacy and safety in KRASG12C -mutant CRC, suggesting the extensive use of this medicine (NCT03785249). Neoadjuvant immunotherapy has improved the prognosis of NSCLC in the past five years, while resistance is an issue that cannot be bypassed. It is never too early to deliberate the combined utilization of KRASG12C inhibitors and immunotherapy. A meta-analysis in 2022 reported that anti-PD-(L)1 therapy with or without chemotherapy achieved more prolonged survival than mono-chemotherapy for KRAS-mutant NSCLC (https://doi.org/10.1007/s00262-021-03031-1). Therefore, combining ICIs and KRASG12C-targeted medicine seems an obvious approach. A preclinical study reported that promoting an antitumor environment and lasting cures were found in mice models treated with sotorasib combined with the anti-PD-1 regimen, supporting the strategy of the combination of ICIs and KRAS inhibitor.4 However, a recent study showed that the successful combination of KRASG12C inhibition (MRTX1257) and ICIs was not universal in the NSCLC tumor models, the synergistic benefit was only seen in the most immunogenic tumor models, and most tumor refractory to ICIs was not resensitized by combination with KRASG12C inhibition.5 Therefore, the confronting questions are: (1) How to select the NSCLC patients who might benefit from the combinational therapy of KRASG12C inhibitors and ICIs? (2) What are the underlying mechanisms and solutions of resistance in the combination of KRASG12C inhibitors and ICIs? Therefore, more efforts are warranted to explore the interactions between KRASG12C inhibitors and cancer immunity. We look forward to the results of KRYSTAL-7 (NCT04613596), a Phase II study evaluating the efficacy and safety of adagrasib monotherapy and in combination with pembrolizumab in cohorts of patients with advanced/metastatic KRASG12C-mutated NSCLC. J.H. and Z.Y. are responsible for the study design. H.T. is responsible for the literature collection and manuscript drafting. H. T. and Z.Y. are responsible for revising the manuscript. J.H. and Z.Y. provide the final approval of the version to be published. All authors read and approved the final manuscript. We sincerely appreciate Doctor Jiachen Xu from the Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China. She offered much professional guidance to this work. The authors declare no competing interests. Not applicable. No original data were generated in this work.

Simple SummaryThe liver is a common metastatic site of non-small cell lung cancer (NSCLC) and is associated with a poor prognosis. Immune checkpoint inhibitors (ICIs), represented by programmed death-1 (PD-1)/ programmed death ligand-1 (PD-L1) inhibitors, have significantly improved efficacy in patients with advanced NSCLC, but the efficacy in patients with NSCLC and liver metastases remains controversial. We aimed to evaluate the efficacy of PD-1/PD-L1 inhibitors in patients with NSCLC and liver metastases in the real-world. In this study, we illustrated that PD-1/PD-L1 inhibitors are effective in NSCLC patients with liver metastases but were inferiorly effective in patients without liver metastases. In addition, PD-L1 expression and CD8+ T cell infiltration may be potential biomarkers for PD-1/PD-L1 inhibitor therapy in NSCLC patients with liver metastases.Background: A controversy exists regarding the efficacy of programmed death-1 (PD-1)/ programmed death ligand-1 (PD-L1) inhibitors for patients with non-small cell lung cancer (NSCLC) and liver metastases. Our study retrospectively evaluated the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients with liver metastases. Methods: This retrospective study included 1627 lung cancer patients who received immunotherapy. Among 648 patients who had advanced NSCLC and received PD-1/PD-L1 inhibitors, 61 had liver metastases and 587 did not have. We analyzed patient characteristics, progression-free survival (PFS) and overall survival (OS). An exploratory analysis of biomarkers including CD4, CD8 and CD68 for efficacy in patients with liver metastases was also performed. Results: In liver metastasis patients receiving PD-1/PD-L1 inhibitors, the objective response rate (ORR) was 29.5%, the disease control rate (DCR) was 72.1%, PFS was 6.4 months and OS was 15.2 months, which were all worse than those of patients without liver metastases (ORR: 35.8%; DCR: 81.8%; PFS: 7.9 months, p = 0.001; OS: 20.6 months, p = 0.008). When compared to non-liver lesions, the ORR (26.2 vs. 39.3%) and DCR (75.4 vs. 88.5%) of liver lesions were lower. During the analysis of PD-L1 expression, 27 PD-L1-positive patients had a longer PFS than 21 patients in the negative group (p = 0.012). Being PD-L1 positive was the independent prognostic indicators for PFS (p = 0.006). Additionally, the PD-L1 and CD8 dual-positive group responded favorably to PD-1/PD-L1 inhibitors. Conclusions: PD-1/PD-L1 inhibitors are effective in liver metastasis–NSCLC patients. However, the efficacy is inferior when compared to those of patients without liver metastases. In NSCLC patients with liver metastases, PD-L1 expression and CD8+ T cell infiltration can predict the response of PD-1/PD-L1-directed immunotherapy.

Differential Efficacy of Pembrolizumab According to Metastatic Sites in Patients With PD-L1 Strongly Positive (TPS ≥ 50%) NSCLC

e20679 Background: Nivolumab (Nivo) is applicable for all metastatic or unresectable non-small cell lung cancer (NSCLC), however only some patients benefit from it. Therefore, identifying biomarkers predicting efficacy is a crucial topic in the “real world’’ setting. We conducted a retrospective study to analyze the impact of metastatic status on the effect of Nivo in NSCLC patients. Methods: This is a retrospective multicenter study conducted by the three medical centers in Japan. All patients treated with Nivo from January 2016 to July 2016 in these centers were retrospectively reviewed. We collected clinical data including age, sex, smoking history, performance status (PS), and metastatic cites (lymph nodes: lym, liver, brain, bone, pleural effusion, and intrapulmonary metastasis: lung) at the time of starting Nivo treatment. We investigated relationship between metastatic sites and progression free survival (PFS) of Nivo. Patients were followed-up until 30th September 2016. Results: Two hundred and one patients treated with Nivo were enrolled. At the time of administration of Nivo, median age was 68 years old, 137 patients were male, 155 patients had history of smoking status, 152 patients were PS 0 or 1, and 46 patients had squamous cell carcinoma (SQ). For all participants, median PFS was 2.5 months. In univariate analysis, female (hazard ratio (HR): 1.43, 95% confidence interval (CI): 1.02-2.00; p = 0.036), never-smoker (HR: 1.51 , 95% CI: 1.05 – 2.17; p = 0. 0262), PS 2 or more (HR: 1.68, 95% CI: 1.17-2.41; p = 0.0045), metastasis to liver (HR: 2.02, 95% CI: 1.30-3.15; p = 0.0015), brain (HR: 1.42, 95% CI: 0.99-2.03; p = 0.0574), bone (HR: 1.42, 95% CI: 1.01-1.98; p = 0.0642), lung (HR: 1.57, 95% CI: 1.13-2.20; p = 0.0076), and malignant pleural effusion (HR: 1.47, 95% CI: 1.06-2.04; p = 0.0195) had significantly correlated with poor PFS. In multivariate analysis, liver metastasis (HR: 1.59, 95% CI: 0.97-2.61; p = 0.0642) and malignant pleural effusion (HR: 1.47, 95%CI: 1.04–2.07; p = 0.0294) had significantly correlated with poor PFS. Conclusions: Liver metastasis and malignant pleural effusion were independent poor prognostic factors of Nivo treatment in NSCLC patients. (UMIN-ID: UMIN000025908)

146 Background: Kentucky has the highest incidence of lung cancer death and despite improvements in treatment and survival, some small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients remain untreated. We looked at factors preventing these patients from receiving necessary treatment. Methods: Data was collected from the Kentucky Cancer Registry (KCR) for SCLC and NSCLC patients from 2012-2015 and included race, gender, age at diagnosis, treatment history, insurance and overall survival. Treatment included any combination of surgery, radiation, chemotherapy or immunotherapy. Patient demographics were summarized based on treatment status and derived odds ratio (OR) and 95% confidence intervals (CI) were reported. Significant associations were assessed at the p < 0.05 level. Results: KCR identified 2,992 SCLC and 13,975 NSCLC patients from 2012-2015. More NSCLC patients [3,608 (25.8%)] were untreated than SCLC patients [621 (20.8%), p < 0.001], and untreated patients overall were more likely to be older, have more comorbidities (SCLC only), and have Medicare, Medicaid or no insurance. Stage at diagnosis was also a factor but differed based on histology. NSCLC stage III and stage IV patients had higher odds of being untreated compared to stage I (Stage III OR: 2.91, 95% CI: 2.57-3.28; Stage IV OR: 4.82, 95% CI: 4.29-5.41) where these odds in SCLC patients were non-significant (Stage III OR: 0.94, 95% CI: 0.56-1.55) or lower (Stage IV OR: 1.61, 95% CI: 1.01-2.55). SCLC patients also had lower odds of delayed treatment (defined as > 4 weeks to treatment) in stage III and stage IV compared to stage I (Stage III OR: 0.33, 95% CI: 0.23-0.48; Stage IV OR: 0.27, 95% CI: 0.20-0.38). Conclusions: This study shows an overall significant number of untreated lung cancer patients with treatment being strongly associated with insurance status, histology and stage at diagnosis. SCLC patients are more likely to be treated than NSCLC, and advanced stage is less a factor in treating SCLC than NSCLC. The difference may be due to the more aggressive nature of SCLC with physicians feeling more urgency to treat SCLC given its rapid progression and chemotherapy sensitivity compared to NSCLC.

BackgroundCamrelizumab plus chemotherapy have been approved as standards for the treatment of advanced non-small cell lung cancer (NSCLC) patients based on two phase III trials. However, clinical trial results may not be representative of the general population, as clinical trials often have specific inclusion and exclusion criteria. Our research aims to investigate the real-world effectiveness and safety of camrelizumab in inoperable or advanced NSCLC patients.MethodsThis multicenter retrospective observational study included inoperable or advanced pathologically confirmed NSCLC patients who received at least one dose of camrelizumab at 22 hospitals. Clinical and follow-up data of camrelizumab were collected retrospectively from the medical records. The primary outcome was the objective response rate (ORR) and secondary outcomes were disease control rate (DCR), 6-month progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Multivariate logistic and Cox regression analyses were applied to identify potential predictive factors of ORR and PFS, respectively.ResultsBetween July 2019 and March 2021, 336 patients were included. Adenocarcinoma was seen in 58.4% and stage IV disease in 69.3%. Twenty-nine (8.6%) had liver metastasis at baseline. Most patients received camrelizumab in the first-line setting (74.1%) and in combination with chemotherapy (60.7%). The ORR was 40.2% [95% confidence interval (CI): 34.9–45.6%] and DCR was 85.1% (95% CI: 81.3–88.9%), while the 6-month PFS and OS rates were 73.0% (95% CI: 67.1–78.0%) and 93.1% (95% CI: 89.8–95.4%), respectively. In multivariate analyses, liver metastasis [odds ratio (OR), 0.324; 95% CI: 0.115–0.915; P=0.033] and increasing lines of camrelizumab treatment (vs. first line, second line: OR, 0.347; 95% CI: 0.162–0.741; P=0.006; ≥ third line: OR, 0.126; 95% CI: 0.043–0.367; P<0.001) were negatively associated, while a longer duration of camrelizumab treatment was positively associated with ORR and PFS. TRAEs were recorded in 164 (48.8%) patients, without new safety signal.ConclusionsWe conducted a comprehensive overview of the effectiveness and safety profile of camrelizumab in a broader NSCLC population in real world NSCLC patients, and subgroup analysis indicated the presence of liver metastasis was associated with worse outcomes.

Brief Report: First-line Pembrolizumab in Metastatic Non-Small Cell Lung Cancer Habouring MET Exon 14 Skipping Mutation and PD-L1 ≥50% (GFPC 01-20 Study)

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

BackgroundLiver metastasis is the most common type of lung cancer metastasis, and is a significant prognostic factor in lung cancer. However, the effect of liver metastases on the efficacy of immune checkpoint inhibitors (ICIs) remains inconsistent and controversial. The aim of this study was to explore the relationship between liver metastases and ICI efficacy in patients with advanced lung cancer based on data from randomized controlled trials (RCTs) and observational studies.MethodsPubMed, EMBASE, Cochrane Library databases, conference proceedings, as well as grey literature websites were searched for eligible studies without language restrict ion. Study quality was assessed using Cochrane tools and the Newcastle–Ottawa Quality Assessment Scale (NOS). Outcomes of interest were overall survival (OS) and progression-free survival (PFS). The difference in efficacy between patients with and without liver metastases was calculated by pooling ratios of hazard ratios (HR), as calculated using the deft approach.ResultsA total of 16 RCTs and 14 observational trials were included. Analyses of RCTs revealed a survival benefit for ICI treatment (i.e., ICI monotherapy, ICI + Chemotherapy, dual ICI therapy and dual ICI + Chemotherapy) versus standard therapies among non-small cell lung cancer (NSCLC) patients with liver metastases (PFS HR, 0.77; 95%CI, 0.61–0.97; OS HR, 0.78; 95%CI, 0.68–0.90). NSCLC patients with liver metastases achieved less PFS benefit and comparable OS benefit from ICI treatment compared with those without liver metastases (ratios of PFS–HRs, 1.19; 95%CI, 1.02–1.39; P=0.029; Ratios of OS–HRs, 1.10; 95%CI, 0.94–1.29; P=0.24). For patients with small cell lung cancer (SCLC), ICI treatment achieved a marginal effect on patients with liver metastases as compared with standard therapies (OS HR, 0.94; 95%CI, 0.73–1.23). SCLC patients with liver metastases benefited less from ICI treatment than patients without liver metastases (ratio of OS–HRs, 1.22; 95%CI, 1.01–1.46; P=0.036). In real-world data analysis, liver metastasis could be used as an independent prognostic risk factor, increasing the risk of death by 21% in lung cancer patients receiving ICI treatment compared with those without liver metastases (OS HR, 1.21; 95%CI, 1.17–1.27; P<0.0001). Subgroup analysis confirmed that this association was not modified by race (Asian vs. Western) or number of treatment lines.ConclusionsThe presence of liver metastases does not significantly influence the OS benefit of ICIs in patients with NSCLC. However, a small amount of data shows that liver metastasis restrains the magnitude of OS benefit in patients with SCLC. Liver metastasis has potential as an independent prognostic risk factor for lung cancer patients receiving ICI treatment in clinical practice.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier (CRD42022306449).

Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

9095 Background: Combination of tyrosine kinase inhibitor (TKI) and chemotherapy has shown improved clinical outcomes in advanced epidermal growth factor receptor ( EGFR) mutated non-small cell lung cancer (NSCLC) patients. We conducted this phase 3, randomized, controlled trial to further investigate the clinical efficacy and safety of gefitinib combined with chemotherapy in EGFR mutated NSCLC patients with brain metastases. Methods: Treatment-naïve, confirmed brain metastases and EGFR sensitive mutated NSCLC patients were screened from six centers in China. The eligible patients were randomly assigned (1:1) to receive gefitinib alone or gefitinib plus pemetrexed-platinum chemotherapy until intracranial progressive diseases, unacceptable adverse, or any cause of death. Theprimary endpoint was intracranial progression-free survival (iPFS), secondary endpoints were PFS, overall survival, intracranial objective response rate, overall objective response rate, and safety. This study is registered at ClinicalTrials. gov, number NCT01951469. Results: From January 2017 to June 2021, 161 patients were randomly assigned to receive gefitinib (n = 81) or gefitinib plus pemetrexed-platinum chemotherapy (n = 80), the median follow-up time was 18.2 (IQR 11.8-29.7) months. The median intracranial PFS was 15.6 (14.3-16.9) months in gefitinib plus chemotherapy group versus 9.1 (8.0-10.2) months in gefitinib group (HR = 0.36, 95% CI, 0.25-0.53, P &lt; 0.001). Similarly, the median PFS was also significantly longer in gefitinib plus chemotherapy than gefitinib alone (16.3 months vs 9.5 months, P &lt; 0.001). In addition, gefitinib plus chemotherapy had better intracranial objective response rate (85.0% versus 63.0%, P = 0.002) and overall objective response rate (80.0% versus 64.2%, P = 0.035) than gefitinib alone. At the data cutoff, 50.3% of patients (35 patients in gefitinib plus chemotherapy group and 46 patients in gefitinib group) had died. The 3-year OS rate was significantly higher in gefitinib plus chemotherapy group (47.4%, 95% CI 36.3-58.7) than in gefitinib group (24.9%, 95% CI 15.1-34.3, P = 0.003). And median overall survival was 35.0 months (95% CI, 28.8-41.3 months) in gefitinib plus chemotherapy group versus 28.9 months (95% CI, 23.4-34.4 months) in gefitinib group (HR = 0.66, 95% CI, 0.42-1.03, P = 0.065). Grade 3 or worse adverse events were more common in gefitinib plus chemotherapy group (40.0% versus 21.0%, P = 0.010), but most of them were manageable. Conclusions: Inuntreated EGFR mutated NSCLC patients with brain metastases, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS and a tendency of OS than gefitinib alone, and could be the optional first-line treatment. Clinical trial information: NCT01951469.

Objective To explore the associations between genetic polymorphisms and haplotypes of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and patients with non small-cell lung cancer (NSCLC).Methods A total of 592 patients with NSCLC and 636 healthy controls were collected.After PCR amplification,TRAIL (G1525A/G1588A/CI595T) gene polymorphisms were detected by using direct sequencing.Haplotype analysis was also performed on all study subjects.Results Frequencies of variant allele (A) and genotype (GA + AA) in TRAIL G1525A were significantly lower in NSCLC patients than in healthy controls (both P＜0.01).Frequencies of variant allele (A) and (T) in TRAIL G1588A and C1595T were also significantly lower in NSCLC patients than those in the healthy controls (both P ＜ 0.01).In the further stratification analysis,frequencies of variant allele (T) and genotype (CT + TT) in TRAIL C1595T significantly differed between (stage Ⅰ + Ⅱ) and (stage Ⅲ + Ⅳ) NSCLC patients [47.89％ vs.58.80％,OR =2.710,95％ confidence interval (CI):1.598-4.596 ; 62.01％ vs.74.65％,OR =2.935,95 ％ CI:1.188-7.249,respectively,both P ＜ 0.05).Moreover,frequency of variant allele (A) in TRAIL G1525A was significantly higher in (stage Ⅲ+ Ⅳ) NSCLC patients than that in (stage Ⅰ + Ⅱ) NSCLC patients (47.54％ vs.40.75％,OR =1.318,95 ％ CI:1.658-1.047,P ＜ 0.05).In addition,TRAIL (G1525A/G1588A/C1595T) genes were found to be in a complete disequilibrium linkage in all study subjects.In contrast with healthy controls,frequency of AAT haplotype was significantly decreased (42.45％ vs.58.23％,95％ CI:1.525-2.824,P ＜0.01),wherease frequency of GAT haplotype was significantly increased in NSCLC patients (9.98％ vs.0.21％,95％ CI:0.015-0.059,P ＜0.01).Conclusion Genetic polymorphisms and haplotypes of TRAIL (G1525A/G1588A/C1595T) genes may be significantly correlated with the susceptibility to NSCLC in Chinese patients. Key words: Non small-cell lung cancer; Tumor necrosis factor; Gene polymorphism

Characterization of Liver Metastasis and Its Effect on Targeted Therapy in EGFR-mutant NSCLC: A Multicenter Study